Female hormone-containing patch

ABSTRACT

Provided herein is a female hormone-containing patch wherein an active ingredient is highly soluble in a pressure-sensitive adhesive layer and the active ingredient is not adsorbed to a backing, and the patch per se can follow the irregularities on the skin surface or body movements. The patch is an external patch containing, as a female hormone, a follicular hormone estradiol and/or its derivative or a progestational hormone norethisterone and/or its derivative. The external patch comprises an acrylic pressure-sensitive adhesive containing 0.01 to 1% by weight of an isocyanate-based crosslinking agent as an essential ingredient.

TECHNICAL FIELD

The present invention relates to an external patch containing a femalehormone useful for prevention or treatment of diseases such asmenopausal syndrome (e.g., headaches, hot flushes, sweating, etc.) whichoften occurs in climacteric or menopausal women, osteoporosis,Alzheimer's disease, arteriosclerosis, and hyperlipemia. Particularly,the present invention relates to an external patch containing, as afemale hormone, a follicular hormone estradiol and/or its derivative ora progestational hormone norethisterone and/or its derivative.

BACKGROUND ART

In recent years, hormone replacement therapy is becoming established asan important method for preventing or treating diseases such asmenopausal syndrome (e.g., headaches, hot flushes, sweating, etc.) whichoften occurs in climacteric or menopausal women, osteoporosis,Alzheimer's disease, arteriosclerosis, and hyperlipemia or for improvingthe QOL of middle-aged and older women.

In order to prevent, treat, or improve such diseases, a hormone drug isorally administered or injected in most cases. However, it is known thatin the case where a female hormone such as a follicular hormone estrogenor a progestational hormone norethisterone is orally administered, thefemale hormone is absorbed from the alimentary canal and is then rapidlymetabolized in the liver. Likewise, it is known that such a femalehormone administered by injection is also rapidly metabolized in theliver. Therefore, in either case, the rate of utilization of the drug issignificantly low.

Further, there is a possibility that not only impaired liver functionbut also side effects such as gallbladder disorder and uterine cancerare produced due to a high metabolic rate in the liver. Therefore, it isnecessary to keep the drug concentration (i.e., a hormone administered)in the body at a minimum. For this reason, methods for administering afemale hormone without allowing the female hormone to pass through thealimentary canal or the liver are being investigated. Among suchmethods, attention is particularly being given to transdermal absorptionpreparations from the viewpoint of excellent sustainability in drugrelease and handleability, and some preparations have already beenstudied.

For example, Japanese Patent Publication No. Hei 6-51623 discloses areservoir-type transdermal absorption preparation in which estradiol andnorethisterone acetate are dissolved in a gel made of hydroxypropylcellulose and ethanol. This reservoir-type transdermal absorptionpreparation controls the release of estradiol and norethisterone acetateby the use of an ethylene-vinyl acetate film. Further, Japanese PatentLaid-Open Publication No. Sho 60-152413 discloses, for example, atransdermal absorption preparation of conjugated estrogens. Thistransdermal absorption preparation contains menthol as a transdermalabsorption promoting agent. However, since these preparations contain avolatile ingredient, there is a fear that drug release characteristicsmay be changed. In addition, the preparation disclosed in JapanesePatent Publication No. Hei 6-51623 involves the risk of causing skintroubles such as rubor because ethanol contained therein is an irritantto the skin.

Further, International Publication No. WO 91/17752, Japanese PatentLaid-Open Publication No. Hei 5-148145, and Japanese Patent Laid-OpenPublication No. 2000-119195 disclose patches manufactured using rubberpressure-sensitive adhesives such as a styrene-isoprene-styrene blockcopolymer. Furthermore, Japanese Patent Laid-Open Publication No. Sho61-155321 discloses a patch including, as a main ingredient, an adhesivebase material containing an adhesive resin material (e.g., polyterpeneresin, hydrocarbon resins), natural rubber or synthetic rubber (e.g.,polyisobutylene, styrene-butylene polymer, styrene-isoprene polymer,styrene-ethylene-butylene polymer, 1,4-polyisoprene) and a polymercapable of swelling in water, such as galactomannan. However, sincethese patches are manufactured using natural rubber or synthetic rubberas a pressure-sensitive adhesive, they are not suitable for prolongedskin application from the viewpoint of the characteristics of naturalrubber or synthetic rubber.

In order to solve such a problem, preparations manufactured usingacrylic pressure-sensitive adhesives enabling prolonged application arebeing investigated. As for estradiol, for example, Japanese PatentLaid-Open Publication No. Hei 3-44327, Translated National Publicationof Patent Application No. Hei 7-501335, Translated National Publicationof Patent Application No. Hei 9-503217, and Translated NationalPublication of Patent Application No. Hei 9-505554 disclose preparationsmanufactured using acrylic pressure-sensitive adhesives. Each of thepreparations contains its own solvent and absorption accelerator agentto improve the transdermal absorbability of estradiol. However, thesepreparations are still not perform sufficient transdermal absorption forpractical use, because they do not perform enough drug release dependingon a solvent and an absorption accelerator agent or some of them areirritants to the skin and they have the risk of causing skin troublessuch as rubor as a result of prolonged application.

It is generally difficult to allow an effective amount of drug topermeate through the skin because the skin tissue of a living bodybasically has a defense function to prevent the entrance of foreignsubstances into the living body. In order to solve such a problem, anabsorption accelerator agent may be added. However, addition of anabsorption promoting agent tends to increase the degree of skinirritation in most cases.

As for norethisterone, for example, Japanese Patent Laid-OpenPublication No. Hei 4-342532 discloses a patch manufactured using anacrylic pressure-sensitive adhesive comprising 2-ethylhexyl acrylate andN-vinyl-2-pyrrolidone. However, since this preparation containsN-vinyl-2-pyrrolidone in a high concentration, norethisterone as a basisis dissolved in the pressure-sensitive adhesive, thus resulting in poorreleasability of norethisterone from the preparation. In addition, thispreparation has a problem in that it causes strong physical irritationto the skin due to its excessive adhesive strength. Therefore, thepreparation cannot be used for prolonged and continuous administration.

Moreover, in the case where an external preparation is administered inhormone replacement therapy, it is necessary to apply the externalpreparation for a long period of time to maintain an effective bloodlevel of a drug. In order to apply the external preparation for a longperiod of time, it is necessary to improve the adhesive strength of abase material of the external preparation. In addition, it isparticularly necessary to enhance the anchor effect of apressure-sensitive adhesive on the irregularities of the skin surface inorder to increase a holding power. The anchor effect of apressure-sensitive adhesive on the irregularities of the skin surfacecan be enhanced by increasing the activity of a polymer compound as anadhesive base material. However, by doing so, there is a possibilitythat the cohesive strength of the polymer compound is lowered so thatcohesion failure occurs, thus resulting in the remaining of thepressure-sensitive adhesive on the skin after peeling-off of theexternal preparation. Therefore, it is necessary to control the anchoreffect of the pressure-sensitive adhesive and the cohesive strength ofthe pressure-sensitive adhesive to allow the external preparation'to beapplied for a long period of time.

In many articles, it has already become apparent that the flexibility ofa backing of an external patch has a strong bearing on an increase ofthe transdermal drug absorption. Examples of a backing having physicalproperties adequate for this purpose include low-density polymer films,non-woven fabrics, and woven fabrics. It is necessary for them to have afree volume sufficient to obtain flexibility. However, when the freevolume of the backing is too large, there is a problem in that drugreleasability is lowered after the external patch is stored for a longperiod of time due to the adsorption of a drug to the backing layer, sothat such an external patch cannot deliver satisfactory performance.

DISCLOSURE OF THE INVENTION

In view of the above fact, it is therefore an object of the presentinvention to provide an external patch containing a female hormone andsatisfying the following points (1) to (4):

-   (1) having improved drug releasability per unit area;-   (2) having a low degree of skin irritation;-   (3) having an improved adhesive strength enough to withstand    prolonged application while preventing cohesive failure from    occurring when the external patch is peeled off after the completion    of prolonged application; and-   (4) having a flexible backing enabling the transdermal absorbability    of a drug to be improved without the drug being adsorbed to the    backing.

Specifically, it is an object of the present invention to provide anexternal patch containing, as a female hormone, a follicular hormoneestradiol and/or its derivative or a progestational hormonenorethisterone and/or its derivative.

In order to achieve the above object, the present inventors haveintensively investigated, and as a result, they have found that by usingan acrylic pressure-sensitive adhesive containing, as an essentialingredient, 0.01 to 1% by weight of an isocyanate-based crosslinkingagent to form an acrylic pressure-sensitive adhesive layer and allowing0.5 to 10% by weight of a female hormone as an active ingredient to becontained in the acrylic pressure-sensitive adhesive layer, it ispossible to obtain a favorable external patch.

Further, they have also found, in the case where a female hormone to becontained in the external patch is a follicular hormone estradiol and/orits derivative, that crotamiton and oleic acid are effective incontrolling the distribution or diffusion of estradiol and/or itsderivative to or in the skin, that crotamiton and oleic acid arepreferably contained in the acrylic pressure-sensitive adhesive layer atoptimum ratios, thereby reducing skin irritation, and that a laminatestructure comprising a polyethylene terephthalate film and a flexiblepolymer film, a non-woven fabric, or a woven fabric can be effectivelyused as a backing.

Furthermore, they have also found, in the case where a female hormone tobe contained in the external patch is a progestational hormonenorethisterone and/or its derivative, that a distribution coefficientbetween the preparation and the skin is an important factor, thatisopropyl myristate is effective in controlling the distributioncoefficient of norethisterone contained in the acrylicpressure-sensitive adhesive, and that isopropyl myristate is preferablycontained in the acrylic pressure-sensitive adhesive layer at an optimumratio, thereby reducing skin irritation. These findings have led to thecompletion of the present invention.

According to a first aspect of the present invention based on the basicconcept provided by the invention, there is provided an estradiol(follicular hormone)-containing external patch comprising a backing anda pressure-sensitive adhesive layer, wherein the pressure-sensitiveadhesive layer is made of an acrylic pressure-sensitive adhesivecontaining 0.01 to 1% by weight of an isocyanate-based crosslinkingagent as an essential ingredient and contains 0.5 to 10% by weight ofestradiol and/or its derivative as an active ingredient, 0.1 to 10% byweight of crotamiton, and 0.1 to 10% by weight of oleic acid.

That is, the first aspect of the present invention is characterized inthat a pressure-sensitive adhesive layer is made of an acrylicpressure-sensitive adhesive containing 0.01 to 1% by weight of anisocyanate-based crosslinking agent as an essential ingredient andcontains estradiol and/or its derivative as an active ingredient, andfurther contains oleic acid and crotamiton at specific ratios.

According to a second aspect of the present invention based on the basicconcept provided by the invention, there is provided a norethisterone(progestational hormone)-containing external patch comprising a backingand a pressure-sensitive adhesive layer, wherein the pressure-sensitiveadhesive layer is made of an acrylic pressure-sensitive adhesivecontaining 0.01 to 1% by weight of an isocyanate-based crosslinkingagent as an essential ingredient and contains 1 to 30% by weight ofisopropyl myristate as a distribution coefficient control agent and 0.5to 10% by weight of norethisterone and/or its derivative as an activeingredient.

That is, the second aspect of the present invention is characterized inthat a pressure-sensitive adhesive layer is made of an acrylicpressure-sensitive adhesive containing 0.01 to 1% by weight of anisocyanate-based crosslinking agent as an essential ingredient and aspecific amount of isopropyl myristate as a distribution coefficientcontrol agent is contained in the acrylic pressure-sensitive adhesive,thereby improving the transdermal absorbability of an active ingredientcontained in the pressure-sensitive adhesive layer and reducing skinirritation.

In the external patches of the first and second aspects of the presentinvention, it is more preferred that the backing be a laminate structurecomprising a polyethylene terephthalate film having a thickness of 0.1to 10 μm and a flexible polymer film, a non-woven fabric, or a wovenfabric having a thickness of 1 to 200 μm.

By using such a backing, it is possible to prevent estradiol and/or itsderivative or norethisterone and/or its derivative as an activeingredient of the external patch from being adsorbed to the backing, andas a result, the active ingredient is very effectively released.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of an external patch of the presentinvention.

FIG. 2 is a graph, which shows the result of Test Example 1 in which thelevel of estradiol in the blood was measured in rats.

FIG. 3 is a graph, which shows the result of Test Example 2 in which thelevel of estradiol in the blood was measured in rats.

FIG. 4 is a schematic view of an apparatus for use in carrying out arelease test in Test Example 3.

FIG. 5 is a graph, which shows the result of Test Example 3 carried outusing an external patch of Example 1.

FIG. 6 is a graph, which shows the result of Test Example 3 carried outusing an external patch of Example 4.

FIG. 7 is a graph, which shows the result of Test Example 3 carried outusing an external patch of Comparative Example 6.

FIG. 8 is a graph, which shows the result of Test Example 3 carried outusing an external patch of Comparative Example 7.

FIG. 9 is a graph, which shows the result of Test Example 3 carried outusing an external patch of Comparative Example 8.

FIG. 10 is a graph, which shows the result of Test Example 4 in which anin-vitro permeation test was carried out using a rat to measure theamount of permeation.

FIG. 11 is a graph, which shows the result of Test Example 5 in whichthe blood level of norethisterone was measured in rats.

FIG. 12 is a graph, which shows the result of Test Example 6 carried outusing an external patch of Example 5.

FIG. 13 is a graph, which shows the result of Test Example 6 carried outusing an external patch of Comparative Example 12.

FIG. 14 is a graph, which shows the result of Test Example 6 carried outusing an external patch of Comparative Example 13.

FIG. 15 is a graph, which shows the result of Test Example 6 carried outusing an external patch of Comparative Example 14.

DESCRIPTION OF THE SYMBOLS IN THE DRAWINGS

A: backing

1: flexible film

2: drug non-adsorptive layer

3: pressure-sensitive adhesive layer

4: release liner

5: patch

6: water

7: glass plate

8: stirrer

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinbelow, the present invention will be described in detail.

As adhesive base materials used in manufacturing an external patch,natural rubber, synthetic rubber pressure-sensitive adhesives, acrylicpressure-sensitive adhesives, and silicon pressure-sensitive adhesivesare generally known. The present inventors have found that in the casewhere natural rubber or a synthetic rubber pressure-sensitive adhesiveis used as an adhesive base material of an external patch, thereleasability of a female hormone as an active ingredient contained in apressure-sensitive adhesive layer is lowered due to a strong interactionbetween the natural rubber or the synthetic rubber pressure-sensitiveadhesive and the female hormone.

In addition, since natural rubber and synthetic rubberpressure-sensitive adhesives are inherently hydrophobic, they are notresistant to sweat and water. Therefore, in hot and humid surroundingsor during taking a bath or exercise, there is a possibility that sweator water enters between the pressure-sensitive adhesive layer and theskin, thus resulting in a reduction in the migration of a drug to theskin or separation of the external patch from the skin. From the fact,it can be said that such an external patch manufactured using naturalrubber or a synthetic rubber pressure-sensitive adhesive as an adhesivebase material is not suitable for. prolonged application that is one ofthe requirements of a preparation of the present invention.

Further, in the case where a silicon pressure-sensitive adhesive is usedas an adhesive base material, final material composition becomesspecific. Since this becomes a factor of an increase in cost, a siliconpressure-sensitive adhesive is not preferable. As a result ofinvestigation, the present inventors have found that an acrylicpressure-sensitive adhesive is most preferable as an adhesive basematerial for use in manufacturing the external patch of the presentinvention containing a female hormone as an active ingredient.

Examples of a monomer constituting the acrylic pressure-sensitiveadhesive include acrylic acid, vinyl acetate, and acrylic esters such asethyl acrylate and 2-ethylhexyl acrylate.

The amount of each of the monomer components to be mixed isappropriately determined according to, for example, desired physicalproperties of an acrylic pressure-sensitive adhesive to be obtained, but2-ethylhexyl acrylate is preferably contained in an amount of 5 to 50%by weight, acrylic acid is preferably contained in an amount of 1 to 10%by weight, ethyl acrylate is preferably contained in an amount of 5 to50% by weight, and vinyl acetate is preferably contained in an amount of5 to 50% by weight.

In the meantime, in hormone replacement therapy, it is necessary tomaintain or sustain an effective blood level of an active ingredient.Therefore, administration of an external preparation requires that apatch should be applied for a long period of time. Improvement in theadhesive strength of a patch, in particular, improvement in the holdingpower of an external patch requires enhancement of the anchor effect ofa pressure-sensitive adhesive on the irregularities of the skin surface.In order to enhance such an anchor effect, it is necessary to increasethe creep of a polymer compound as an adhesive base material. However,by doing so, there is a possibility that the cohesive strength of thepolymer compound is decreased so that cohesive failure occurs when theexternal patch is peeled off, thus resulting in the remaining of thepressure-sensitive adhesive on the skin after peeling-off of theexternal patch. For this reason, it is necessary to control the anchoreffect and the cohesive strength of the pressure-sensitive adhesive.

In view of such a problem, the present inventors have made an intensivestudy, and as a result, they have found that by loosely crosslinking apolymer compound component as an adhesive base material by the use of asmall amount of crosslinking agent, it is possible to allow the adhesivebase material to exert an effective anchor effect on the skin whilepreventing the occurrence of cohesive failure when an external patch ispeeled off.

Such a crosslinking agent is not limited to any specific one as long asit can effectively crosslink an acrylic pressure-sensitive adhesive. Ithas been found that, among such crosslinking agents, an isocyanate-basedcrosslinking agent is most preferable. The amount of the crosslinkingagent to be mixed is in the range of 0.01 to 1% by weight, preferably inthe range of 0.1 to 0.7% by weight. If the amount of the crosslinkingagent to be mixed is less than 0.01% by weight, the occurrence ofcohesive failure is not effectively prevented. On the other hand, if theamount of the crosslinking agent to be mixed exceeds 1% by weight, thecreep of the polymer compound component as an adhesive base material isdecreased so that an effective anchor effect cannot be obtained.

The external patch of the present invention is manufactured by usingsuch an acrylic pressure-sensitive adhesive as a base material andallowing a female hormone as an active ingredient to be contained in theacrylic pressure-sensitive adhesive.

Hereinbelow, each of the aspect of the external patch of the presentinvention will be explained individually.

The first aspect of the present invention is characterized in that theabove-mentioned pressure-sensitive adhesive layer is made of an acrylicpressure-sensitive adhesive containing 0.01 to 1% by weight of anisocyanate-based crosslinking agent as an essential ingredient, contains0.5 to 10% by weight of estradiol and/or its derivative as an activeingredient, and further contains oleic acid and crotamiton at specificratios.

In this case, the amount of estradiol and/or its derivative to be mixedis not particularly limited and varies depending on a pressure-sensitiveadhesive component to be used and the amount of oleic acid andcrotamiton to be mixed (which will be described later), but ispreferably in the range of 0.5 to 10% by weight. If the amount ofestradiol and/or its derivative to be mixed is less than 0.5% by weight,the level of estradiol and/or its derivative in the blood does notbecome sufficient. On the other hand, even if the amount of estradioland/or its derivative to be mixed exceeds 10% by weight, an increase inthe mixing ratio thereof does not proportionately increase the level ofestradiol and/or its derivative in the blood. In addition, there is anundesired possibility that estradiol and/or its derivative iscrystallized in the pressure-sensitive adhesive.

Crotamiton imparts high solubility to estradiol and/or its derivative asan active ingredient to prevent the crystallization of estradiol and/orits derivative in the pressure-sensitive adhesive layer. Further,crotamiton increases the concentration of a drug being in solution andhaving a good diffusion activity, and controls the distribution of thedrug to the skin according to a relative concentration to estradiol.

The amount of crotamiton to be mixed is in the range of 0.1 to 10% byweight, preferably in the range of 0.5 to 5% by weight. If the amount ofcrotamiton to be mixed is less than 0.1% by weight, the above effectscannot be obtained. On the other hand, if the amount of crotamiton to bemixed exceeds 10% by weight, the solubility of estradiol contained inthe preparation is excessively increased so that the distribution ofestradiol to the skin is reduced. In addition, there is an undesiredpossibility that skin irritation occurs due to excessive crotamiton.

Oleic acid is used together with crotamiton. Oleic acid breaks thestructure of lipid membrane of corneous cells having the greatest skin'sdefense function, that is, a barrier function to increase the diffusioncoefficient of estradiol in the skin. In this way, oleic acid exerts anabsorption promoting effect.

The amount of oleic acid to be mixed varies depending on the amount ofcrotamiton to be mixed together with oleic acid, but is in the range of0.1 to 10% by weight, preferably in the range of 0.5 to 5% by weight.

If the amount of oleic acid to be mixed is less than 0.1% by weight,such an absorption promoting effect cannot be obtained. On the otherhand, even if the amount of oleic acid to be mixed exceeds 10% byweight, an increase in the amount of oleic acid to be mixed does notproportionately enhance the absorption promoting effect.

The second aspect of the present invention is characterized in that apressure-sensitive adhesive layer is made of an acrylicpressure-sensitive adhesive containing 0.01 to 1% by weight of anisocyanate-based crosslinking agent as an essential ingredient andcontains 1 to 30% by weight of isopropyl myristate as an essentialingredient and norethisterone and/or its derivative as an activeingredient.

Norethisterone and/or its derivative has a high degree of solubility inthe acrylic pressure-sensitive adhesive, which leads to poorreleasability of a drug from the pressure-sensitive adhesive. However,by allowing isopropyl myristate to be contained in the adhesive basematerial, it becomes possible to control the distribution ofnorethisterone to the adhesive base material, thereby improving thereleasability of the drug.

The amount of an active ingredient norethisterone and/or its derivativeto be mixed is not particularly limited and varies depending on apressure-sensitive adhesive component to be used, the amount ofisopropyl myristate to be mixed, and the structure of a backing to beused (which will be described later), but is in the range of 0.5 to 10%by weight, preferably in the range of 1 to 7% by weight, more preferablyin the range of 3.0 to 5% by weight. If the amount of norethisteroneand/or its derivative to be mixed is less than 0.5% by weight, the levelof norethisterone and/or its derivative in the blood does not becomesufficient. On the other hand, even if the amount of norethisteroneand/or its derivative to be mixed exceeds 10% by weight, an increase inthe mixing ratio thereof does not proportionately increase the level ofnorethisterone and/or its derivative in the blood. In addition, there isan undesired possibility that norethisterone and/or its derivative iscrystallized in the pressure-sensitive adhesive.

The amount of isopropyl myristate to be mixed is in the range of 1 to30% by weight, preferably in the range of 3 to 20% by weight, morepreferably in the range of 5 to 10% by weight. If the amount ofisopropyl myristate to be mixed is less than 1% by weight, the aboveeffect cannot be obtained. On the other hand, if the amount of isopropylmyristate to be mixed exceeds 30% by weight, it becomes difficult tomaintain the cohesive strength of the pressure-sensitive adhesive evenwhen an excessive amount of crosslinking agent is mixed, thereby, forexample, causing a problem in that the pressure-sensitive adhesiveremains on the skin surface after the external patch is peeled off.

In the meantime, it has been already apparent that the flexibility ofthe backing of an external patch strongly contribute to the improvementof the transdermal absorbability of an active ingredient contained in apressure-sensitive adhesive layer. Examples of a backing having physicalproperties adequate for such a purpose include low-density polymerfilms, non-woven fabrics, and woven fabrics. In the case where they areused singly as a backing, it is necessary for them to have a sufficientvolume to obtain flexibility. Therefore, an external patch manufacturedin such a manner involves a problem in that drug releasability islowered after the external patch is stored for a long period of time dueto the occurrence of adsorption of a drug to the backing, so that theexternal patch may not be satisfactory. In the case of the externalpatch of the present invention containing a female hormone as an activeingredient, it is necessary to avoid lowering of drug releasability asfar as possible.

In view of such a problem, the present inventors have made investigationof a backing suitable for an external patch containing a female hormoneas an active ingredient. As a result, it has been confirmed that the useof a laminate structure comprising a drug non-adsorptive layer having avery thin and dense structure and a flexible film capable of followingthe irregularities on the skin or body movements as a backing makes itpossible to prevent the adsorption of the active ingredient to thebacking, thereby improving the transdermal absorbability of a drug.

FIG. 1 shows the structure of such a backing. As shown in FIG. 1, abacking A to be used for the external patch of the present invention isa laminate structure comprising a flexible film 1 and a drugnon-adsorptive layer 2 having a thin and dense structure. The externalpatch of the present invention has a structure in which apressure-sensitive adhesive layer 3 containing an active ingredient islaminated on the drug non-adsorptive layer 2 and a release liner 4 islaminated on the pressure-sensitive adhesive layer 3.

As described above, the backing A to be used for the external patch ofthe present invention is characterized in that the drug non-adsorptivelayer 2 having a thin and dense structure is provided on thepressure-sensitive adhesive layer to prevent the adsorption of an activeingredient to the backing and the flexible film 1 is provided to allowthe external patch to follow the irregularities on the skin or bodymovements.

The drug non-adsorptive layer is not limited to any specific one as longas it has a dense structure, can be formed into a thin film, and doesnot interact with the components of the pressure-sensitive adhesivelayer, such as an active ingredient. Examples of such a drugnon-adsorptive layer include metal films, evaporated metals, andhigh-density polymer films (polyethylene terephthalate film). Amongthem, a polyethylene terephthalate film is preferable from the viewpointof versatility and manufacturing costs. The thickness of the drugnon-adsorptive layer e.g., a polyethylene terephthalate film ispreferably in the range of about 0.1 to 20 μm. If the thickness of thepolyethylene terephthalate film exceeds 20 μm, the external patch cannotfollow the irregularities on the skin or body movements due to thestiffness of the polyethylene terephthalate film, and therefore thetransdermal absorbability of an active ingredient contained in thepressure-sensitive adhesive layer is lowered.

On the other hand, the flexible film to be laminated on the drugnon-adsorptive layer is not limited to any specific one as long as itcan follow the irregularities on the skin or body movements. Examples ofsuch a flexible film include woven fabrics, non-woven fabrics, andpolymer films made of polyethylene, polypropylene, polyurea,polyurethane, polyester, polyvinyl alcohol, polyvinyl chloride, orpolymeric elastomers. The thickness of the film is in the range of about1 to 200 μm, preferably in the range of about 2 to 100 μm, morepreferably in the range of about 5 to 50 μm.

If the thickness of the flexible film layer is less than 1 μm, it isdifficult to apply a preparation to the skin because the preparation isbent or warped when the release liner is removed due to the lack ofelasticity. On the other hand, if the thickness of the flexible filmlayer exceeds 200 μm, it becomes difficult for a preparation to followthe irregularities on the skin surface or body movements so that thetransdermal absorbability of an active ingredient is lowered.

The external patch according to the present invention can bemanufactured, for example, in such a manner as described below. 39% byweight of 2-ethyihexyl acrylate, 1% by weight of acrylic acid, 40% byweight of ethyl acrylate, and 20% by weight of vinyl acetate are mixed,and are then subjected to polymerization for 24 hours at 60° C. underreduced pressure in ethyl acetate by the use of benzoyl peroxide as apolymerization initiator to obtain an ethyl acetate solution of anacrylic pressure-sensitive adhesive. A female hormone estradiol and/orits derivative or norethisterone and/or its derivative as an activeingredient and desired components are added to the acrylicpressure-sensitive adhesive solution and then stirred. The thus obtainedmixture is applied on a release liner and dried, and then a backing islaminated thereon. The thus resultant product is cut into a desired sizeto obtain an external patch.

In the external patch of the present invention manufactured in such amanner, since a female hormone such as estradiol and/or its derivativeor norethisterone and/or its derivative as an active ingredientcontained in the pressure-sensitive adhesive layer is well dissolved inthe pressure-sensitive adhesive layer, the active ingredient is notadsorbed to the backing. In addition, the external patch per se canfollow the irregularities on the skin surface or body movements.Therefore, the external patch can provide an excellent transdermalabsorbability of an active ingredient contained in thepressure-sensitive adhesive layer and can withstand prolongedapplication. Such an external patch is useful for prevention ortreatment of diseases such as menopausal syndrome (e.g., headaches, hotflushes, sweating, etc.) which often occurs in climacteric or menopausalwomen, osteoporosis, Alzheimer's disease, arteriosclerosis, andhyperlipemia.

EXAMPLES

Hereinbelow, the present invention will be described in more detail withreference to Examples. Incidentally, the word “part” in the followingExamples and Comparative Examples means “part by weight.”

A: Estradiol-containing Patch

Examples 1 to 4

According to the manufacturing method described above and a formulashown in Table 1, estradiol-containing external patches of the presentinvention were obtained. Each of the estradiol-containing externalpatches of Examples 1 to 3 was manufactured by laminating apressure-sensitive adhesive layer on a polyethylene terephthalate filmconstituting a backing (a laminate structure) having a predeterminedthickness and cutting the thus obtained product into a desired size.

Note that the estradiol-containing external patch of Example 4 wasmanufactured by subjecting a low-density polyethylene film having athickness of 50 μm as a backing to aluminum vapor deposition, laminatinga pressure-sensitive adhesive layer on the aluminum-deposited surface ofthe low-density polyethylene film, and cutting the thus obtained productinto a desired size.

TABLE 1 Examples Constituent (part) 1 2 3 4 Estradiol 5.00 5.00 5.005.00 Crotamiton 2.50 2.50 2.50 2.50 Oleic acid 2.50 2.50 2.50 2.50Acrylic pressure-sensitive 89.80 89.80 89.80 89.80 adhesiveIsocyanate-based crosslinking 0.20 0.20 0.20 0.20 agent BackingThickness (μm) Polyethylene terephthalate film 3 5 10 — Low-densitypolyethylene film 50 50 50 — Aluminum-evaporated low-density — — — 50polyethylene film

Comparative Examples 1 to 8

According to the manufacturing method described above and a formulashown in Table 2, estradiol-containing external patches of ComparativeExamples 1 to 8 were obtained. Each of the estradiol-containing externalpatches of Comparative Examples 1 to 5 was manufactured by laminating apressure-sensitive adhesive layer on a polyethylene terephthalate filmconstituting a backing having a predetermined thickness and cutting thethus obtained product into a desired size.

Note that Comparative Example 6 used a low-density polyethylene filmhaving a thickness of 50 μm as a backing (a monolayer structure),Comparative Example 7 used a polyvinyl 15 chloride film having athickness of 50 μm as a backing (a monolayer structure), and ComparativeExample 8 used a polyurethane film having a thickness of 50 μm as abacking (a monolayer structure). Each of the estradiol-containingexternal patches of Comparative Examples 6 to 8 was manufactured bylaminating a pressure-sensitive adhesive layer on the backing andcutting the thus obtained product into a desired size.

Comparative Examples Constituent (part) 1 2 3 4 5 6 7 8 Estradiol 5.05.0 5.0 5.0 5.0 5.0 5.0 5.0 Crotamiton — 2.5 — 2.5 2.5 2.5 2.5 2.5 Oleicacid — — 2.5 2.5 2.5 2.5 2.5 2.5 Acrylic pressure-sensitive adhesive94.8 92.3 92.3 89.8 89.8 89.8 89.8 89.8 Isocyanate-based crosslinkingagent 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Backing Thickness (μm)Polyethylene terephthalate film 3 3 3 30 50 — — — Low-densitypolyethylene film 50 50 50 50 50 50 — — Polyvinyl chloride film — — — —— — 50 — Polyurethane film — — — — — — — 50

Test Example 1 Measurement of Level of Estradiol in Blood of Rats (Part1)

Four rats were used as one test group. The back region of each of therats was shaved, and then the external patches of Example 1 andComparative Examples 1, 2, and 3 each having a size of 9 cm² wereapplied to the back regions shaved of the rats, respectively. The bloodof each of the rats was sampled with the lapse of time to measure thelevel of estradiol in the blood by RIA method. The measurement resultsare shown in FIG. 2.

As is apparent from FIG. 2, in each of the cases of the external patchof Comparative Example 1 containing no oleic acid and crotamiton and theexternal patches of Comparative Examples 2 and 3 each containing eitheroleic acid or crotamiton, virtually no change was observed in the levelof estradiol in the blood with the lapse of time. On the other hand, inthe case of the external patch of Example 1 containing both of oleicacid and crotamiton, the level of estradiol in the blood becameobviously high. From the results, it has been confirmed that theexternal patch of the present invention is useful.

Test Example 2 Measurement of Level of Estradiol in Blood of Rats (Part2)

The back region of each of rats was shaved, and then the externalpatches of Examples 1 and 4 and Comparative Examples 4 and 5 each havinga size of 9 cm² were applied to the back regions shaved of the rats,respectively. The blood of each of the rats was sampled with the lapseof time to measure the level of estradiol in the blood by RIA method.The measurement results are shown in FIG. 3. Incidentally, four ratswere used as one test group.

As is apparent from FIG. 3, in the cases of the external patch ofExample 1 of the present invention manufactured using, as a backing, alaminate structure comprising a thin polyethylene terephthalate filmhaving a thickness of 3 μm and a low-density polyethylene film having athickness of 50 μm and the external patch of Example 4 of the presentinvention manufactured using, as a backing, a low-density polyethylenefilm which had been subjected to aluminum vapor deposition, the level ofestradiol in the blood remained at an obviously higher level by virtueof the flexibility of the backing as compared to the cases of theexternal patch of Comparative Example 4 manufactured using, as abacking, a laminate structure comprised of a polyethylene terephthalatefilm having a thickness of 30 μm and a low-density polyethylene filmhaving a thickness of 50 μm and the external patch of ComparativeExample 5 manufactured using, as a backing, a laminate structurecomprised of a polyethylene terephthalate film having a thickness of 50pm and a low-density polyethylene film having a thickness of 50 μm.

Test Example 3 Active Ingredient Release Test after Storage (Part 1)

The external patches of Examples 1 and 4 and Comparative Examples 6, 7,and 8 were stored for 6 months at 40° C., and were then subjected to arelease test according to a method shown in FIG. 4 to determine theadsorbability of estradiol to the backing. The adsorbability ofestradiol to the backing was evaluated by comparing the releasability ofestradiol between the external patch after 6-month storage and theexternal patch in the initial state after manufacturing. The results areshown in FIGS. 5, 6, 7, 8, and 9.

In each of the cases of the external patch manufactured using alow-density polyethylene film as a backing (Comparative Example 6, FIG.7), the external patch manufactured using a polyvinyl chloride film as abacking (Comparative Example 7, FIG. 8), and the external patchmanufactured using a polyurethane film as a backing (Comparative Example8, FIG. 9), it can be concluded that the releasability of estradiol asan active ingredient was impaired due to the occurrence of adsorption ofestradiol to the backing.

On the other hand, in each of the cases of the external patch of Example1 manufactured using, as a backing, a laminate structure comprising apolyethylene terephthalate film and a low-density polyethylene film(FIG. 5) and the external patch of Example 4 manufactured using, as abacking, a polyethylene terephthalate film which had been subjected toaluminum vapor deposition (FIG. 6), the releasability of estradiol wasnot impaired even after the external patch was stored for 6 months at40° C. From the result, it was confirmed that the adsorption ofestradiol to the backing did not occur.

B: Norethisterone-containing Patch

Examples 5 to 7

According to the manufacturing method described above and a formulashown in Table 3, norethisterone acetate-containing external patches ofthe present invention were obtained. Each of the norethisteroneacetate-containing external patches of Examples 5 to 7 was manufacturedby laminating a pressure-sensitive adhesive layer on a polyethyleneterephthalate film constituting a backing (a laminate structure) havinga predetermined thickness and cutting the thus obtained product into adesired size.

TABLE 3 Examples Constituent (part) 5 6 7 Norethisterone acetate 5.005.00 5.00 Isopropyl myristate 5.00 10.00 20.00 Acrylicpressure-sensitive adhesive 89.80 84.80 74.80 Isocyanate-basedcrosslinking agent 0.20 0.20 0.20 Backing Thickness (μm) Polyethyleneterephthalate film 3 3 3 Low-density polyethylene film 50 50 50

Comparative Examples 9 to 14

According to the manufacturing method described above and a formulashown in Table 4, norethisterone acetate-containing external patches ofComparative Examples 9 to 14 were obtained. Each of the norethisteroneacetate-containing external patches of Comparative Examples 9 to 14 wasmanufactured by laminating a pressure-sensitive adhesive layer on apolyethylene terephthalate film constituting a backing having apredetermined thickness and cutting the thus obtained product into adesired size.

Note that Comparative Example 12 used a low-density polyethylene filmhaving a thickness of 50 μm as a backing (a monolayer structure),Comparative Example 13 used a polyvinyl chloride film having a thicknessof 50 μm as a backing (a monolayer structure), and Comparative Example14 used a polyurethane film having a thickness of 50 μm as a backing (amonolayer structure). Each of the norethisterone acetate-containingexternal patches of Comparative Examples 12, 13, and 14 was manufacturedby laminating a pressure-sensitive adhesive layer on the backing andcutting the thus obtained product into a desired size.

TABLE 4 Comparative Examples Constituent (part) 9 10 11 12 13 14Norethisterone acetate 5.00 5.0 5.0 5.0 5.0 5.0 Isopropyl myristate —10.00 10.00 10.00 10.00 10.00 Acrylic pressure-sensitive 94.8 84.8084.80 84.80 84.80 84.80 adhesive Isocyanate-based 0.2 0.2 0.2 0.2 0.20.2 crosslinking agent Backing Thickness (μm) Polyethylene terephthalate3 30 50 — — — film Low-density polyethylene 50 50 50 50 — — filmPolyvinyl chloride film — — — — 50 — Polyurethane film — — — — — 50

Test Example 4 In Vitro Permeation Test in Rat

The abdominal region of a rat was shaved, and then the abdominal skinwas extracted. The extracted skin was placed in a Franz cell, and theinside of the cell was filled with 10 mL of phosphate buffered saline (areceptor solution). In a water jacket, a hot water having a temperatureof 37° C. was circulated. Each of the external patches of Examples 5, 6,and 7 and Comparative Example 9 was stamped into a circular shape (1.77cm²), and was then applied to the extracted skin of the rat. Thereceptor solution was sampled with the lapse of time to measure theamount of norethisterone that passed through the skin and eluted intothe receptor solution according to a liquid chromatography method.

The result is shown in FIG. 10. As is apparent from FIG. 10, in the caseof the external patch of Comparative Example 9 containing no isopropylmyristate as a distribution coefficient control agent in the adhesivebase material, the permeation amount of norethisterone was extremelysmall as compared to the cases of Examples 5, 6, and 7. From theseresults, it can be concluded that isopropyl myristate contained in theadhesive base material has the effect of promoting the absorption ofnorethisterone.

Test Example 5 Measurement of Level of Norethisterone in Blood of Rats

Four rats were used as one test group. The back region of each of therats was shaved, and then the external patches of Example 5 andComparative Examples 10 and 11 each having a size of 9 cm2 were appliedto the back regions shaved of the rats, respectively. The blood of eachof the rats was sampled with the lapse of time to measure the level ofnorethisterone in the blood according to a gas chromatography method.The measurement results are shown in FIG. 11.

As is apparent from FIG. 11, in the case of the external patch ofExample 5 manufactured using, as a backing, a laminate structurecomprising a polyethylene terephthalate film having a thickness of 3 μmand a low-density polyethylene film having a thickness of 50 μm, thelevel of norethisterone in the blood remained at an obviously higherlevel by virtue of the flexibility of the backing as compared to thecases of the external patch of Comparative Example 10 manufacturedusing, as a backing, a laminate structure comprising a polyethyleneterephthalate film having a thickness of 30 μm and a low-densitypolyethylene film having a thickness of 50 μm and the external patch ofComparative Example 11 manufactured using, as a backing, a laminatestructure comprising a polyethylene terephthalate film having athickness of 50 μm and a low-density polyethylene film having athickness of 50 μm.

Test Example 6 Active Ingredient Release Test after Storage (Part 2)

The external patches of Example 5 and Comparative Examples 12, 13, and14 were stored for 6 months at 40° C., and were then subjected to arelease test according to a method shown in FIG. 4 to determine theadsorbability of norethisterone to the backing. The adsorbability ofnorethisterone to the backing was evaluated by comparing thereleasability of norethisterone between the external patch after 6-monthstorage and the external patch in the initial state after manufacturing.The results are shown in FIGS. 12, 13, 14, and 15.

In each of the cases of the external patch manufactured using alow-density polyethylene film as a backing (Comparative Example 12, FIG.13), the external patch manufactured using a polyvinyl chloride film asa backing (Comparative Example 13, FIG. 14), and the external patchmanufactured using a polyurethane film as a backing (Comparative Example14, FIG. 15), it can be concluded the releasability of norethisterone asan active ingredient was impaired due to the occurrence of adsorption ofnorethisterone to the backing.

On the other hand, in the case of the external patch of Example 5manufactured using a laminate structure comprising a polyethyleneterephthalate film and a low-density polyethylene film as a backing(FIG. 12), the releasability of norethisterone was not impaired evenafter the external patch was stored for 6 months at 40° C. From theresult, it was confirmed that the adsorption of norethisterone to thebacking did not occur.

INDUSTRIAL APPLICABILITY

As has been described above, the external patch according to the presentinvention has a pressure-sensitive adhesive layer made of an acrylicpressure-sensitive adhesive containing 0.01 to 1% by weight of anisocyanate-based crosslinking agent as an essential ingredient, and thepressure-sensitive adhesive layer contains a female hormone. In the casewhere the female hormone to be contained in the pressure-sensitiveadhesive layer is estradiol and/or its derivative, crotamiton and oleicacid are further contained in the pressure-sensitive adhesive layer atspecific ratios.

In the case where the female hormone to be contained in thepressure-sensitive adhesive layer is norethisterone and/or itsderivative, isopropyl myristate is further contained in thepressure-sensitive adhesive layer at a specific ratio.

By using, as a backing, a laminate structure comprising a drugnon-adsorptive layer and a flexible film for the external patch of thepresent invention, it becomes possible to highly dissolve a drug in thepressure-sensitive adhesive and stabilize the drug. In addition, itbecomes also possible to improve the transdermal absorbability of amedical ingredient and release the drug stably for a long period of timewithout adsorption of the drug to the backing.

The invention claimed is:
 1. An external patch comprising a backing anda pressure-sensitive adhesive layer, wherein the backing is a laminatestructure comprising a flexible film as an outer layer and a drugnon-adsorptive layer, wherein said flexible film has a thickness of 1 to200 μm and is selected from at least one of the group consisting ofwoven fabrics, non-woven fabrics and polymer films; wherein said drugnon-adsorptive layer has a thickness of 0.1 to 10 μm and is apolyethylene terephthalate film; and wherein said pressure-sensitiveadhesive layer is made of an acrylic pressure-sensitive adhesive, saidpressure-sensitive adhesive layer being adjacent to said drugnon-adsorptive layer and not adjacent to the flexible film, wherein theadhesive layer comprises: 0.01 to 1% by weight of an isocyanate-basedcrosslinking agent; 0.5 to 10% by weight of estradiol and/or aderivative of estradiol as an active ingredient dissolved in theadhesive layer; 0.5 to 10% by weight of crotamiton; and 0.1 to 10% byweight of oleic acid, and wherein the active ingredient is not adsorbedto the backing.
 2. An external patch comprising a backing and apressure-sensitive adhesive layer, wherein the backing is a laminatestructure comprising a flexible film as an outer layer and a drugnon-adsorptive layer, wherein said flexible film has a thickness of 1 to200 μm and is selected from at least one of the group consisting ofwoven fabrics, non-woven fabrics and polymer films; wherein said drugnon-adsorptive layer has a thickness of 0.1 to 10 μm and is apolyethylene terephthalate film, said pressure-sensitive adhesive layerbeing adjacent to said drug non-adsorptive layer and not adjacent to theflexible film; and wherein said pressure-sensitive adhesive layer ismade of an acrylic pressure-sensitive adhesive, wherein the adhesivelayer comprises: 0.01 to 1% by weight of an isocyanate-basedcrosslinking agent; 1 to 30% by weight of isopropyl myristate as adistribution coefficient control agent; and 0.5 to 10% by weight ofnorethisterone and/or a derivative of nonethisterone as an activeingredient, and wherein the active ingredient is not adsorbed to thebacking.
 3. An external patch comprising a backing and apressure-sensitive adhesive layer, wherein the backing is a laminatestructure comprising a low density polyethylene flexible film as anouter layer having a thickness of 1 to 200 μm and a drug non-adsorptivelayer, wherein said drug non-adsorptive layer has a thickness of 0.1 to10 μm and is a polyethylene terephthalate film; and wherein saidpressure-sensitive adhesive layer is made of an acrylicpressure-sensitive adhesive, said pressure-sensitive adhesive layerbeing adjacent to said drug non-adsorptive layer and not adjacent to theflexible film, wherein the adhesive layer consists of: 0.01 to 1% byweight of an isocyanate-based crosslinking agent; 0.5 to 10% by weightof estradiol and/or a derivative of estradiol as an active ingredient;0.5 to 10% by weight of crotamiton; and 0.1 to 10% by weight of oleicacid, and wherein the active ingredient is not adsorbed to the backing.4. An external patch comprising a backing and a pressure-sensitiveadhesive layer, wherein the backing is a laminate structure comprising alow density polyethylene flexible film as an outer layer having athickness of 1 to 200 μm and a drug non-adsorptive layer, wherein saiddrug non-adsorptive layer has a thickness of 0.1 to 10 μm and is apolyethylene terephthalate film, and wherein said pressure-sensitiveadhesive layer being adjacent to said drug non-adsorptive layer and notadjacent to the flexible film; and wherein said pressure-sensitiveadhesive layer is made of an acrylic pressure-sensitive adhesive,wherein the adhesive layer consists of: 0.01 to 1% by weight of anisocyanate-based crosslinking agent; 1 to 30% by weight of isopropylmyristate as a distribution coefficient control agent; and 0.5 to 10% byweight of norethisterone and/or a derivative of nonethisterone as anactive ingredient, and wherein the active ingredient is not adsorbed tothe backing.
 5. An external patch for application to a skin surfaceconsisting of: a) a low density polyethylene flexible film as anoutermost layer, which is oriented farthest from the skin surface whenapplied to the skin surface, wherein said flexible film has a thicknessof 1 to 200 μm; b) a drug non-adsorptive as a layer adjacent to theflexible film layer, wherein said drug non-adsorptive layer has athickness of 0.1 to 10 μm and is a polyethylene terephthalate film; c) apressure-sensitive adhesive layer adjacent to the drug non-adsorptivelayer and not adjacent to the flexible film, wherein the adhesive layerconsists of 0.01 to 1% by weight of an isocyanate-based crosslinkingagent, 0.5 to 10% by weight of estradiol and/or a derivative ofestradiol as an active ingredient, 0.5 to 10% by weight of crotamiton,and 0.1 to 10% by weight of oleic acid; and d) a release layer adjacentto the pressure-sensitive adhesive layer and next to the skin surfacewhen applied to the skin surface, and wherein the active ingredient isnot adsorbed to the backing.
 6. An external patch for application to askin surface consisting of : a) a low density polyethylene flexible filmas an outermost layer, which is oriented farthest from the skin surfacewhen applied to the skin surface, wherein said flexible film has athickness of 1 to 200 μm; b) a drug non-adsorptive as a layer adjacentto the flexible film layer, wherein said drug non-adsorptive layer has athickness of 0.1 to 10 μm and is a polyethylene terephthalate film; c) apressure-sensitive adhesive layer adjacent to the drug non-adsorptivelayer and not adjacent to the flexible film, wherein the adhesive layerconsists of 0.01 to 1% by weight of an isocyanate-based crosslinkingagent; 1 to 30% by weight of isopropyl myristate as a distributioncoefficient control agent, and 0.5 to 10% by weight of norethisteroneand/or a derivative of nonethisterone as an active ingredient; and d) arelease layer adjacent to the pressure-sensitive adhesive layer and nextto the skin surface when applied to the skin surface, and wherein theactive ingredient is not adsorbed to the backing.
 7. The external patchaccording to claim 1 or 2, wherein the flexible film is low densitypolyethylene film.
 8. The external patch according to claim 1 or 2,wherein the acrylic component of the acrylic pressure-sensitive adhesiveis selected from least one of the following compounds: 2-ethylhexylacrylate, acrylic acid, ethyl acrylate, vinyl acetate, and an acrylicester.